MF59 Adjuvant Enhances Diversity and Affinity of Antibody-Mediated Immune Response to Pandemic Influenza Vaccines

Abstract

Oil-in-water adjuvants have been shown to improve immune responses against pandemic influenza vaccines as well as reduce the effective vaccine dose, increasing the number of doses available to meet global vaccine demand. Here, we use genome fragment phage display libraries and surface plasmon resonance to elucidate the effects of MF59 on the quantity, diversity, specificity, and affinity maturation of human antibody responses to the swine-origin H1N1 vaccine in different age groups. In adults and children, MF59 selectively enhanced antibody responses to the hemagglutinin 1 (HA1) globular head relative to the more conserved HA2 domain in terms of increased antibody titers as well as a more diverse antibody epitope repertoire. Antibody affinity, as inferred by greatly diminished (≥10-fold) off-rate constants, was significantly increased in toddlers and children who received the MF59-adjuvanted vaccine. Moreover, MF59 also improved antibody affinity maturation after each sequential vaccination against avian H5N1 in adults. For both pandemic influenza vaccines, there was a close correlation between serum antibody affinity and virus-neutralizing capacity. Thus, MF59 quantitatively and qualitatively enhances functional antibody responses to HA-based vaccines by improving both epitope breadth and binding affinity, demonstrating the added value of such adjuvants for influenza vaccines.

Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells

“…Stem-binding Abs identified following vaccination were found using phage display libraries (2-4) or immortalization of memory B cells (5), and it has therefore not been possible to assess their overall contribution to the vaccine-induced response. Interestingly, a recent study (16) showed that the MF59 adjuvant can enhance the diversity and affinity of the antibody response to pandemic influenza vaccine, and another study showed that DNA priming can enhance antibody responses to the H5N1 vaccine (17).…”

MF59^® Adjuvanted Seasonal and Pandemic Influenza Vaccines

“…7,8) As the HA1 contains the viral receptor binding domain and principal neutralizing epitopes, this qualitative shift in the antibody repertoire may explain the more cross-reactive adjuvanted response to antigenically divergent in‰uenza viral strains. In addition, the antibodies also exhibit a higher a‹nity for properly folded HA, seen in higher equilibrium levels and a tenfold increased resistance to dissociation under treatment with 7M urea, as measured by surface plasmon resonance.…”

“…The slower dissociation was highly correlated with increasing neutralizing antibody titer. 7,8) SEASONAL ATIV-OLDER ADULTS ATIV was developed to improve the lower antibody response and suboptimal e‹cacy of TIV in older adults-estimated to be 50％ in the only placebocontrolled trial in this age group. 9,10) Numerous small comparative trials in older adults (over 65 years of age) have shown that hemagglutination inhibition (HI) and microneutraliziation (MNT) antibody responses to ATIV are approximately 1.5 fold higher than to identical but unadjuvanted TIV, with strain to strain variability of the geometric mean ratios (GMR) ranging from 1.2 1.8 fold higher.…”

Vaccinology in the era of high-throughput biology

“…Fluarix ) or a cold-adapted live attenuated vaccine, administered as a nasal spray (e.g. FluMist w ); which time points to analyse (clonal expansion of plasmablasts in the blood of young adults peaks at day 7 post-trivalent influenza vaccine (TIV) vaccination [6], whereas monocyte-and interferonrelated signatures peak at earlier time points [7]); the use of adjuvants such as MF-59 w [8]; which influenza strains to immunize subjects with, the seasonal ones [7,[9][10][11][12], or specific strains such as the 2009 H1N1 pandemics strain [11] and the avian-origin strains [13,14]; and, finally, the population target, which may include those with suboptimal responses or from different age groups, such as children [15], elderly or immunocompromised patients.…”